Although considerable advances have been made in identifying genes involved in psychiatric disease, the genetic complexity and phenotypic variability associated with these disorders significantly hinders our comprehension of these illnesses. The use of endophenotypes as indices of disease risk is a novel way to explore the genetic determinants associated with psychiatric disorders. We have a unique and very powerful family-based resource, which contains a vast array of pre-existing genetic and phenotypic information from which we can build on to define molecular pathways associated with complex diseases, including those of neurological origin. This project will use a novel strategy to define a role for microRNAs in brain-related endophenotypes and thus help to elucidate the mechanisms by which psychiatric disorders develop. Using state-of-the-art technologies we will identify and quantitate novel and known microRNAs in 1,000 Mexican Americans from approximately 40 families. These potent regulators of gene expression are likely to influence multiple genetic pathways associated with neurobiology. We will use previously collected phenotypic data on a wide range of neuroanatomical and neurocognitive traits to investigate the potential for involvement of microRNAs in psychiatric disorders. Further, we will use existing whole-genome genotypic data and transcriptional profiles to investigate upstream modulation of and downstream regulation by microRNAs, thereby gaining an important understanding of the genetic basis of these important molecules. To gain an understanding of miRNAs that might be implicated in a psychiatric disorder, we will perform similar analyses in a smaller population consisting of individuals affected with bipolar I disorder, unaffected siblings and unrelated controls. We will begin to explore the downstream consequences of aberrant miRNA expression using gain and loss of function analyses to strengthen our understanding of miRNA biology. The power of this project to identify mechanisms for genetic regulation involved in brain-related endophenotypes and psychiatric disease is unprecedented. With advancing technologies and recent scientific discoveries the potential to unravel the mysteries of the human genome is now stronger than ever. Our approach will combine several layers of genetic information to elucidate the molecular pathology of psychiatric diseases and their endophenotypes, thereby paving the way for the discovery of novel therapeutic and prevention strategies for these debilitating illnesses.